Brain ventricles are a highly conserved system of cavities that contain cerebrospinal fluid and are believed to protect the brain from injury, remove waste, and carry chemical signals. Blockage of free fluid circulation leads to hydrocephalus, one of the most common birth defects. Additionally, abnormalities in brain ventricle structure and size have been extensively documented in individuals affected with schizophrenia and autism. This exploratory proposal seeks to understand the genetic basis for brain ventricle formation, using the zebrafish as a model, and definition of a set of brain ventricle mutants as the foundation for the study. The longer term goal is to understand the role that genes corresponding to these mutants play in formation of the brain ventricular system, and to address whether their misfunction contributes to the etiology of autism, schizophrenia and related disorders. The zebrafish has proven an excellent genetic and molecular model for issues in developmental biology including brain formation and function, and has served as a model for many human diseases. It is hypothesized that ventricle morphology and function may alter brain function, and conversely, that ventricle formation and maintenance is dependent on normal brain function. In preliminary studies, the timecourse of brain ventricle formation in the zebrafish has been described and 3 mutants with defects in brain ventricle development have been examined. It is proposed, firstly, to continue characterization of these mutants by analyzing (i) molecular and cell biological changes relative to wild type fish embryos, (ii) cell autonomy of their function and (iii) epistatic interactions between them (hierarchy of function). Secondly, 28 mutants reported to have brain ventricle phenotypes, but otherwise unstudied, that were derived from chemical mutagenesis screens will be further analyzed. Additional mutants will be defined in collaboration with Dr. Nancy Hopkins, MIT, by screening through 275 retroviral insertional mutants for which candidate genes have been identified. Brain ventricle mutants will be categorized as a prelude to cloning corresponding genes. This study will define a large collection of genes required for normal brain ventricle formation, and which may display abnormal activity in patients with mental health disorders. [unreadable] [unreadable]